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Randy L. Jensen

✓ In this article, the author provides a brief description of the role of hypoxia in the tumorigenesis of gliomas and suggests potential ways of exploiting this role to design treatment modalities. Tumor hypoxia predicts the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiation therapy, invasive potential, and decreased patient survival for many human malignancies. Various methods of measurement of tumor hypoxia are discussed, including direct measurement and imaging methods.

The role of hypoxia-responsive molecules, especially hypoxia-inducible factor-1 (HIF-1), in glioma tumorigenesis is explored. Treatment modalities regulated by hypoxia are proposed and some potential strategies reviewed. The progression of a low-grade astrocytoma to a glioblastoma multiforme may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of cells that overexpress hypoxia-responsive molecules, such as HIF-1. In this model, intratumoral hypoxia causes genetic changes that produce a microenvironment that selects for cells of a more aggressive phenotype.

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Randy L. Jensen

Object

The term “cauda equina syndrome” (CES) has been used to describe the signs and symptoms in patients with compressive neuropathy of multiple lumbar and sacral roots. This syndrome is well known as an indication for surgical intervention in treating lumbar spine disease, but relatively unknown as a postoperative complication following surgery for disease. In this study the author describes two cases of CES that occurred following uneventful lumbar spine procedures—one microdiscectomy and one decompressive laminectomy.

Methods

Preoperative, operative, and postoperative management is discussed and the relevant literature reviewed. One patient suffered perineal numbness and bowel and bladder difficulty following a decompressive laminectomy. Postoperative imaging studies were negative for residual lesion and the treatment goal pursued was partial long-term resolution of symptoms. The second patient had progressive numbness and weakness in the lower extremities. Results of urgent postoperative magnetic resonance imaging studies were inconclusive and repeated exploration was performed within hours of the initial procedure. The patient made a full recovery, although the intraoperative findings did not reveal a clear cause of the patient's symptoms.

Conclusions

Postoperative symptoms of partial or complete CES represent a medical emergency, especially if they are progressive. It is necessary to perform urgent postoperative imaging in patients, but the results are not always helpful. Surgical exploration is warranted if a mass lesion is demonstrated on imaging studies or if symptoms progress and the disease origin is not clear based on available information.

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Brian T. Ragel and Randy L. Jensen

In this article the authors provide a brief description of the current understanding of meningioma genetics. Chromosome 22 abnormalities, especially in the Neurofibromatosis Type 2 (NF2) gene, have been associated with meningioma development. Loss of heterozygosity of chromosome 22 occurs in approximately 60% of meningiomas; however, loss of NF2 gene function occurs in only one third of these lesions. This discrepancy supports the theory that a second tumor suppressor gene exists on chromosome 22, and the authors introduce several possible gene candidates, including BAM22, LARGE, INI1, and MN1 genes. Deletions of 1p have also been shown to correlate with meningioma progression. The genetic similarities and differences among sporadic, NF2-associated, pediatric, and radiation-induced meningiomas are discussed, with the observation that the nonsporadic meningiomas have a higher incidence of multiple chromosomal abnormalities at presentation. Ultimately, a better understanding of the molecular pathways of meningioma tumorigenesis will lead to new, successful treatments.

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Matthew Womeldorff, David Gillespie, and Randy L. Jensen

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Nataliya Smith, Debra Saunders, Randy L. Jensen, and Rheal A. Towner

OBJECTIVE

High-grade gliomas, such as glioblastoma (GBM), are devastating tumors with a very poor prognosis. Previously the authors have found that the nitrone compound OKN-007 (OKlahoma Nitrone 007; or disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is effective against high-grade gliomas in various GBM rodent and human xenograft models. The purpose of the present study was to assess the levels of the lipopolysaccharide-binding protein (LBP) in rodent gliomas treated with OKN-007 as well as determine the expression of LBP in human gliomas.

METHODS

Microarray analysis was done to assess altered gene expression following OKN-007 administration in an F98 glioma model. An enzyme-linked immunosorbent assay was incorporated to assess LBP levels in glioma tissues, as well as blood serum, comparing results in OKN-007–treated and untreated tumor-bearing animals. Immunohistochemistry was used to assess LBP levels in varying grades of human glioma tissue sections.

RESULTS

Upon further assessment of gene expression fold changes in F98 gliomas in rats that received or did not receive OKN-007, it was found that the gene for LBP was significantly downregulated by OKN-007. Further investigation was done to see whether levels of LBP were affected by OKN-007 treatment in F98 gliomas. It was found that LBP could be detected not only in glioma tissue but also in blood serum of F98 glioma-bearing rats and that OKN-007 decreased the levels of LBP. It was also found that LBP levels are highly expressed in human high-grade glioma tissues.

CONCLUSIONS

LBP could potentially be used as a serum diagnostic marker of treatment response in high-grade gliomas.

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Randy L. Jensen, Scott Soleau, Mihir K. Bhayani, and Dustin Christiansen

Object. Vascular endothelial growth factor (VEGF) has been implicated in meningioma tumorigenesis and growth. The production of VEGF is regulated by hypoxia inducible factor—1α (HIF-1α), especially under conditions of hypoxia. In this study, the authors examine the expression of HIF-1α and VEGF in meningiomas, with a special emphasis on conditions of hypoxia, such as preoperative embolization, and on in vitro studies in cultured cells.

Methods. Meningiomas obtained in 142 patients were studied using immunohistochemical methods to detect HIF-1α and the results were correlated with the extent or lack of preoperative embolization and expression of VEGF. Primary meningioma cell cultures were established and cell culture experiments were performed using a hypoxia chamber to stimulate HIF-1α and VEGF production. Expression of HIF-1α in primary meningioma cell cultures was measured using immunoblot assays. The VEGF secretion was measured using enzyme-linked immunosorbent assay.

Half of the meningiomas studied were positive for HIF-1α, with a strong correlation between complete embolization and HIF-1α expression. Most of the meningiomas studied expressed VEGF protein, and VEGF expression did not correlate with the degree of embolization. A strong correlation was found between VEGF and HIF-1α expression in immunohistochemical studies. Secretion of VEGF is increased by hypoxia and growth factor stimulation. In meningiomas, growth factors stimulate HIF-1α expression. The role of hypoxia is less clear.

Conclusions. The expression of HIF-1α is increased by complete preoperative embolization of meningiomas. The expression of HIF-1α also correlates with VEGF secretion in meningiomas. Growth factor and hypoxic stimulation both contribute to VEGF control, but which is most important (or whether both are equally important) will require further studies.

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Michael T. Bounajem, Michael Karsy, and Randy L. Jensen

OBJECTIVE

Primary brain tumors are the most common cause of cancer-related deaths in children and pose difficult questions for the treating physician regarding issues such as the risk/benefit of performing a biopsy, the accuracy of monitoring methods, and the availability of prognostic indicators. It has been recently shown that tumor-specific DNA and proteins can be successfully isolated in liquid biopsies, and it may be possible to exploit this potential as a particularly useful tool for the clinician in addressing these issues.

METHODS

A review of the current literature was conducted by searching PubMed and Scopus. MeSH terms for the search included “liquid biopsy,” “brain,” “tumor,” and “pediatrics” in all fields. Articles were reviewed to identify the type of brain tumor involved, the method of tumor DNA/protein analysis, and the potential clinical utility. All articles involving primary studies of pediatric brain tumors were included, but reviews were excluded.

RESULTS

The successful isolation of circulating tumor DNA (ctDNA), extracellular vesicles, and tumor-specific proteins from liquid biopsies has been consistently demonstrated. This most commonly occurs through CSF analysis, but it has also been successfully demonstrated using plasma and urine samples. Tumor-related gene mutations and alterations in protein expression are identifiable and, in some cases, have been correlated to specific neoplasms. The quantity of ctDNA isolated also appears to have a direct relationship with tumor progression and response to treatment.

CONCLUSIONS

The use of liquid biopsies for the diagnosis and monitoring of primary pediatric brain tumors is a foreseeable possibility, as the requisite developmental steps have largely been demonstrated. Increasingly advanced molecular methods are being developed to improve the identification of tumor subtypes and tumor grades, and they may offer a method for monitoring treatment response. These minimally invasive markers will likely be used in the clinical treatment of pediatric brain tumors in the future.

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Nataliya Smith, Debra Saunders, Randy L. Jensen, and Rheal A. Towner

OBJECTIVE

High-grade gliomas, such as glioblastoma (GBM), are devastating tumors with a very poor prognosis. Previously the authors have found that the nitrone compound OKN-007 (OKlahoma Nitrone 007; or disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is effective against high-grade gliomas in various GBM rodent and human xenograft models. The purpose of the present study was to assess the levels of the lipopolysaccharide-binding protein (LBP) in rodent gliomas treated with OKN-007 as well as determine the expression of LBP in human gliomas.

METHODS

Microarray analysis was done to assess altered gene expression following OKN-007 administration in an F98 glioma model. An enzyme-linked immunosorbent assay was incorporated to assess LBP levels in glioma tissues, as well as blood serum, comparing results in OKN-007–treated and untreated tumor-bearing animals. Immunohistochemistry was used to assess LBP levels in varying grades of human glioma tissue sections.

RESULTS

Upon further assessment of gene expression fold changes in F98 gliomas in rats that received or did not receive OKN-007, it was found that the gene for LBP was significantly downregulated by OKN-007. Further investigation was done to see whether levels of LBP were affected by OKN-007 treatment in F98 gliomas. It was found that LBP could be detected not only in glioma tissue but also in blood serum of F98 glioma-bearing rats and that OKN-007 decreased the levels of LBP. It was also found that LBP levels are highly expressed in human high-grade glioma tissues.

CONCLUSIONS

LBP could potentially be used as a serum diagnostic marker of treatment response in high-grade gliomas.

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Sarah Nguyen, Kyril L. Cole, Kathleen H. Timme, and Randy L. Jensen

Neurosurgery residents spend a significant amount of their time teaching patients, families, students, residents, and other health professionals. To help ensure competence in their residents’ teaching abilities, many specialties have established formal residents-as-teachers (RAT) curricula; however, such formalized curricula are often lacking in neurosurgery programs. The authors’ goal was to develop and implement a formal RAT curriculum, designed with neurosurgery residents’ other responsibilities in mind, to improve residents’ formal and informal teaching abilities. Here, the authors report on the design of a formalized teaching curriculum tailored for the needs of neurosurgical residents, with a focus on deliberate practice and minimal time needed for preparation. The curriculum, designed using Kern’s 6 steps of curriculum design as a framework, comprises 5 lecture series spread over 3 years, repeated twice through a resident’s training, with each lecture series outlined with its respective topics and objectives. Opportunities for observed teaching as well as informal and formal evaluation will be provided to residents. The program will be evaluated on a yearly basis using direct and anonymized resident feedback on the RAT curriculum. Measures of program success will also include pre- and postprogram medical student and peer evaluation of residents. These data will be used for continual improvement of the curriculum as it is implemented. Successes and shortcomings of this program will be disseminated by publication, presentations, and placement on the authors’ department website and social media. This paper may serve as a foundation for other neurosurgical programs to develop RAT curricula for greater enhancement of resident teaching abilities.

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Dennis C. Shrieve, Lisa Hazard, Kenneth Boucher, and Randy L. Jensen

Object. Benign meningiomas have been shown to be equally well controlled with single-dose radiosurgery (15 Gy) and fractionated doses of 54 Gy in 30 fractions after adequate follow up. For a subset of patients with meningioma, the optic apparatus is dose limiting when considering single-dose stereotactic radiosurgery, with tolerance estimated to be 8 to 10 Gy. Recently, hypofractionated regimens have been used to treat benign meningiomas with a small number of fractions. An analysis of the expected efficacy of hypofractionation compared with the estimated optic tolerance to fractionated radiotherapy was undertaken.

Methods. Using the assumption that 15 Gy in one fraction and 54 Gy in 30 fractions are isoeffective for control of benign meningioma, an α/β for meningioma is calculated to be 3.28 Gy. Invoking a 10% error for these doses (15 Gy ± 10% is equivalent to 54 Gy ± 10%) results in upper and lower limits of the estimate for α/β of 3.85 Gy and 2.7 Gy. Using these estimates, isoeffect curves for control of meningioma were constructed for fraction numbers of one to 45. Best estimates of optic nerve/chiasm tolerance to single doses of radiation are 8 to 10 Gy, with the reported incidence of optic neuropathy increasing significantly at higher doses. This is consistent with the optic ret model, which also predicts for optic tolerance following fractionated radiotherapy. Comparison of optic tolerance and estimates of efficacious doses at fraction numbers between one and 30 were made. Statistical estimates of patient numbers and duration of follow up required to rule out optic neuropathy following radiotherapy were made. Single doses of radiation required to treat benign meningioma optimally (13.5–16.5 Gy) clearly exceed the estimated and reported clinical tolerance of the optic nerves and chiasm. The application of equivalent biological doses in a small number of fractions continues to exceed optic tolerance until at least 25 fractions are applied.

Conclusions. The use of small numbers of fractions to treat patients with meningioma when portions of optic nerve or chiasm receive full dose may result in undertreatment of the tumor and/or exceeding optic nerve tolerance. In such cases standard fractionation is recommended. Ruling out a low, yet unacceptable, risk of optic neuropathy may require the close study of many patients with long-term follow-up evaluation.